Innovative strategies for tobacco cessation must be considered. Currently, there are 44 million smokers in the US and 1.2 billion smokers world-wide. Although 22 million smokers try to quit smoking each year, only 3-5% are successful in becoming sustained abstainers. Even with the best treatments which combine pharmacotherapy and behavioral treatment, on average long-term abstinence rates are around 25%. Furthermore, at any one time, only 4-20% of smokers are ready to quit smoking. Unless there is a dramatic change in the trends, by year 2025, it is anticipated that 10 million smokers will die per year world-wide from tobacco-caused diseases. Recent publications and discussions have focused on the tobacco product as target for reducing tobacco-related morbidity and mortality by either reducing toxicants and/or nicotine in the product or by altering the delivery system. These types of potential reduced exposure products (PREPs) have been increasingly surfacing in the U.S. market. A strategy to utilize these products in conjunction with existing pharmaceutical products may provide a novel method to help people who are unable to quit through traditional cessation methods or may improve on existing pharmacotherapies. Examining PREPs that primarily manipulate nicotine dose and speed of nicotine delivery would be particularly instructive in understanding potential treatment targets and methods that will enhance cessation success. To this end, this propose study will randomize cigarette smokers to: 1) Lower nitrosamines, high and rapid nicotine delivery oral tobacco products for 4 weeks and then nicotine patch alone for an additional 4 weeks;2) denicotinized cigarettes (which provides sensory behavioral aspects of smoking) plus nicotine patch for 4 weeks and nicotine patch alone for an additional 4 weeks;or 3) nicotine gum or lozenge plus nicotine patch for 4 weeks and then nicotine patch alone for 4 weeks, with the goal of abstinence. Outcome measures will include withdrawal symptoms and craving, time to lapse to usual brand of cigarettes, cessation assessed at the end of treatment and at 12 and 24 weeks post-treatment, and biomarkers of exposure and toxicity. Predictors of treatment response for each of the treatment conditions will also be explored. The results of this project should provide valuable information on innovative methods for reducing tobacco toxicant exposure and promoting cessation and a better understanding of the underlying mechanisms of and contributors to treatment response. Furthermore, the results from this study will provide guidance for future large, longer-term clinical trials to test promising interventions and will also provide guidance for policy directions. PUBLIC HEALTH RELEVANCE: This project will examine innovative strategies for cigarette smoking cessation. Currently marketed tobacco products that result in reduced tobacco toxicant exposure will be used in conjunction with medicinal nicotine to provide a novel method to help smokers quit smoking. These tobacco products will vary in level of nicotine dose and speed of nicotine delivery and smokers will graduate from these products to using solely medicinal nicotine products prior to complete cessation. The results of this study will provide useful information on directions to pursue to improve our pharmacotherapies and behavioral treatments and to better understand the various aspects of addiction.